Viracept contaminant could be widespread, FDA says

Not only have the latest Viracept contamination cases prompted new guidelines and restricted use of the HIV drug, but according to a representative of the FDA's Center for Drug Evaluation and Research (CDER), the toxic contaminant could in fact be lurking in a number of drug products that have been on the market for many years. Concern regarding the presence of precisely this type of contaminant in medicinal products prompted an FDA project to establish guidelines dictating limits for such genotoxic compounds for pharmaceutical manufacturers. The guidance, due to be issued in the near future, highlights the agency's view that these impurities represent a pressing problem in pharmaceutical manufacturing, one that has been emphasised by the recent events surrounding the HIV drug, Viracept. The contamination of both the Pfizer and Roche versions of Viracept was caused by ethanol from cleaning products reacting with the drug's active ingredient, nelfinavir mesylate. The reaction in the process machinery caused the formation of ethyl mesylate (EMS), a known carcinogen, mutagen (harmful to DNA) and teratogen (harmful to fetuses). Pfizer has been quick to point out that the levels of EMS found in its version of Viracept were at levels "substantially lower​" than those associated with the total recall of Roche's product across the EU in June. The EMS levels that triggered the Roche recall were caused by human errors in cleaning processes which left large amounts of excess ethanol in the process machinery, which in turn reacted with chemicals during the drug's manufacture. This did indeed lead to a significant spike in EMS levels in certain batches of Roche's Viracept product. However, the critical point to highlight here is that EMS has been present in both the Pfizer and Roche products ever since they entered the market. The levels of EMS found in the drug in its normal condition are admittedly much lower than those that prompted Roche's June recall. However, detailed data regarding just how dangerous the genotoxic compound actually is to humans is very thin on the ground, so it is simply not known what levels could in fact prove harmful. What is perhaps more worrying, however, is the fact that through an interview with a representative of the FDA's Center for Drug Evaluation and Research (CDER), in-PharmaTechnologist.com has learnt that not only could there be numerous drugs out on the market that contain such contaminants, but that regulators have been aware of the problem for several years. "It was a risk-benefit decision" ​ The FDA's reaction to Pfizer's contamination case contrasted starkly with measures taken over in Europe, when EU regulators realised that the safety of Viracept in its normal condition could not be guaranteed. Roche was forced to stop production of the drug and also lost its marketing authorisation, not to mention being instructed to compile registries of Viracept patients stretching back as far as 1998, as well as carrying out toxicology studies to try and pin down just how dangerous EMS could be. Every single patient in the EU was taken off Viracept and switched to an alternative medication. In the US, however, Pfizer and the FDA agreed on measures somewhat more sedate than their European counterparts. The basic guidance is that no new pediatric or pregnant patients should be started on the drug, and any pregnant women currently taking the medication should be switched to an alternative if possible. Aside from these specific patient populations, however, all US Viracept patients are being encouraged to continue with their treatment. Although the two organisations have established interim and long-term specifications to limit the amount of EMS found in US supplies of Viracept from now on, the disparity in reactions on either side of the Atlantic is interesting to note. "This is a judgement call, and different agencies might think differently,"​ said Dr Jeff Murray, deputy director of the CDER's division of antiviral products. "For our patient population here, which is what we have to consider, it was a risk-benefit decision…reasonable agencies come up with slightly different plans for their populations." ​ Murray defended the FDA's decision to keep Viracept on the market, saying that the agency believed it would be better for patients to be exposed to these higher, interim levels of EMS for a short period of time, rather than risk an abrupt medication switch or drug shortage for Viracept patients. The interim EMS limit will be in place for six months, before a final limit is enforced. Any Pfizer Viracept product manufactured from the time of the alert at the start of September onwards must now meet the more stringent criteria of the final EMS limitation. The company is apparently working "diligently​" to address its manufacturing process to reduce the amount of the process impurity that ends up in its final product. Implications widespread? ​ However, putting to one side Pfizer's current damage-limitation activities, Murray mentioned that it is likely that this kind of impurity is in fact present in a variety of pharmaceutical drugs both currently on the market and in development. "There are several drug products on the market that have mesylate, besylate or tosylate salts…these are the type of drug salts that could involve this process impurity, ethyl methanesulfonate,"​ he said. "This involves potentially several different drug products that could finally come under the final [EMS] specification." ​ It appears the FDA, along with is opposite number over in Europe, has been well aware of the existence of such compounds in the drug products it approves, and has spent the last few years trying to compile guidelines to regulate the amount of these genotoxic substances found in drug products. However, it is very difficult to pin down a precise level at which a genotoxic compound can be declared 'safe'. This is reflected in guidance published by the European Medicines Agency (EMEA) back in January, which tackles the problem of genotoxic impurities in medicinal products. ​"According to current regulatory practice it is assumed that (in vivo) genotoxic compounds have the potential to damage DNA at any level of exposure…and that such damage may lead/contribute to tumor development,"​ the document states. "Thus for genotoxic carcinogens it is prudent to assume that there is no discernible threshold and that any level of exposure carries a risk​."​ (emphasis added.) Judging by the difference in reaction to the events of the last few months, however, it would seem that the FDA's evaluation of the risk associated with EMS was somewhat dissimilar to that of the European regulators. "You have to remember this drug's been on the market for 10 years and other drugs with EMS, not just antiretrovirals, have been there a while and quite frankly every lot has not been tested for this impurity and these new stringent standards we're putting in,"​ Murray said. The consequences for other drug products manufactured by Pfizer, Roche, or any other drug manufacturers routinely using ethanol-based cleaning products in their process machinery, are therefore potentially far-reaching. Any manufacturer using ethanol anywhere near these kinds of salts during the production of their drugs should presumably be aware of the possibility that these harmful compounds could be forming during manufacture. Despite numerous attempts, Pfizer could not be reached for comment on the manufacturing processes used for its other drugs prior to going to press. "We are aware of all the drugs that have [these impurities],"​ says Murray. "We have been in contact with many of the sponsors, we are aware of the manufacturing process, so we don't expect [the levels] to be extremely high. ​​"But when we set a final limit for this then the manufacturers are going to need to make sure they are in compliance with the most strict levels." ​ These 'final limits' will come in the form of guidance currently being worked out at the FDA, but as yet unpublished. The Viracept case forced the agency's hand, compelling it to issue specific requirements for this particular drug ahead of time, said Murray. Viracept itself is a fairly old product, and as such the current patient population is relatively small compared to other HIV drugs on the market. However, the number of patients in the US prescribed the drug is still significant, and although figures were not forthcoming from either Pfizer or the FDA, Murray estimated that it was around ten times more that the two or three European countries where it is used the most - translating as tens of thousands of patients. The FDA insists that the measures it has taken regarding Viracept are intended to protect these patients from levels of this impurity that it has now decided are above the danger threshold. However, it will be interesting to see just how many drug products currently on the market will fall foul of the FDA's new impurities guidance when it is eventually issued. A whole host of questions will presumably follow, not least the question of just how exposed generations of patients have been to a variety of low-level toxic compounds hidden in their medication.